Panagiotis Davaris

Enhanced mRNA expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in breast carcinomas is correlated with adverse prognosis

Tissue inhibitor of metalloproteinase‐1 (TIMP‐1) has emerged as a multifunctional protein with the contrasting activities of inhibiting tissue‐degrading enzymes and promoting cellular growth. In an attempt to elucidate the clinical significance of TIMP‐1 in breast cancer, the expression of TIMP‐1 mRNA was evaluated in 117 invasive breast carcinomas by mRNA in situ hybridization, in correlation with clinicopathological parameters, immunohistochemical prognostic factors (Ki‐67, c‐erb‐B‐2, bcl‐2) and clinical outcome. TIMP‐1 was detected in stromal cells in areas within the tumours and at the tumour margin. High TIMP‐1 mRNA expression in the marginal portion of the tumours was significantly correlated with lymph node metastasis (p<0.05) and c‐erbB‐2 expression (p<0.05). On the other hand, increased TIMP‐1 mRNA expression within the tumours showed a statistically significant correlation with ER detection (p<0.01). Multivariate analysis revealed worse survival for patients with high TIMP‐1 mRNA expression in the marginal portion of the tumours; the subgroup of these patients co‐expressing high levels of TIMP‐1 mRNA within the tumours as well had even worse survival (p=0.042). In conclusion, our data support the multifunctional role of TIMP‐1, particularly its growth‐promoting activity, on the basis of its significant correlation with lymph node metastasis and adverse prognosis. In addition to the latter property, a probable association of TIMP‐1 with tumour cell differentiation is suggested by its topographical correlation with ER detection. Copyright

Matrix metalloproteinase-1 and -3 in breast cancer: correlation with progesterone receptors and other clinicopathologic features.

Although matrix metalloproteinases (MMPs) are implicated in breast cancer progression, the contribution of MMP-1 and MMP-3 to this process, has not been thoroughly investigated. Matrix metalloproteinases (MMPs) are important at several points during multistage neoplastic progression. Immunohistochemistry (Strept-ABC-HRP method) and in situ hybridization were performed to detect MMP-1, MMM-3 proteins, and MMP-3 mRNA, respectively, in 77 infiltrative breast carcinomas. MMP-1, MMP-3 protein, and MMP-3 mRNA detection were analyzed in parallel with clinicopathologic features (menopausal status, histological type, nuclear and histological grade, stage) and the immunohistochemical reactivity of estrogen (ER), progesterone (PR) receptors, and c-erbB-2 oncoprotein in breast carcinomas. Statistical analysis was performed using the multiple linear regression test. Immunoreactivity for MMP-1 and MMP-3 was observed in 59 of 77 (77%) and 22 of 77 (28.5%) breast carcinomas and was evaluated separately in cancer cells and in stromal fibroblasts. MMP-3 mRNA was detected in 72 of 77 (93.5%) carcinomas exclusively in stromal cells within the tumors or in the marginal portion of tumors. MMP-1 protein immunoreactivity in stromal fibroblasts but not in cancer cells showed a statistically significant correlation with tumor stage (P=.04). MMP-1 reactivity either in stromal or in cancer cells showed a statistically significant inverse correlation with PR expression (P=.04 and P=.04, respectively). MMP-3 protein immunoreactivity in cancer or stromal cells and MMP-3 mRNA expression was not associated with the clinicopathologic features studied. MMP-3 mRNA was detected more often in ductal carcinomas. These results indicate that MMP-1 may contribute to breast cancer invasiveness. Furthermore, they suggest differential functions for MMP-1 and MMP-3 in breast cancer progression.

Differential Expression of bcl-2 Family Proteins in Bladder Carcinomas: Relationship with Apoptotic Rate and Survival

OBJECTIVE To elucidate the role of various bcl-2 family molecules in the regulation of apoptosis and the progression of urothelial cancer, in relation to standard prognosticators. METHODS Paraffin-embedded archival tissue from 103 N0M0 consecutive patients with invasive bladder cancer (28 T1, 57 T2, 13 T3 and 5 T4) was immunostained for bcl-2, bax, bcl-XL, bcl-Xs, p53, Ki-67 and with an anti-single stranded DNA monoclonal antibody recognizing the apoptotic cells. Survival analysis was restricted to T2-T4 tumours. Patients were followed-up until death (n = 27) or for a mean (+/- S.D.) follow-up of 37.6 (+/- 17.4) months. Within this period, 39 patients relapsed after a mean (+/- S.D.) period of 13.6 (+/- 12.3) months. RESULTS Most tumours were immunoreactive for bax (73.1%) and bcl-XL (80.9%) whereas bcl-2 and bcl-XS expression was comparatively less common (44.4 and 28.9%, respectively). The bcl-XL and bcl-XS positivity was related to high grade (P = 0.007) and advanced stage (P = 0.010), respectively. On the contrary, bax and bcl-2 positivity was unrelated to stage or grade. Apoptotic rate was independently influenced only by p53, bcl-2 and proliferation rate. In multivariate analysis of T2-T4 urothelial carcinomas (UC)s, only bax along with T-category and age were the significant predictors of disease-free survival. Increased apoptosis and T-category were also independently related to the overall survival in T2-T4 UCs. CONCLUSIONS The expression of bcl-2 family members appears to be differentially regulated in association with UC evolution. Most importantly, bax immunostaining offers additional information to that provided by traditional prognosticators, with regard to disease-free survival of T2-T4 UCs.

Prognostic significance of histologic host response in cancer of the large bowel

Histologic material from 156 patients treated with surgery for cancer of the large bowel was studied with regard to tumor host interaction and with particular emphasis on the reactions of the regional lymph nodes.

Rapid urease test is less sensitive than histology in diagnosing Helicobacter pylori infection in patients with non-variceal upper gastrointestinal bleeding.

Background and Aims : The validity of the rapid urease (CLO) test to diagnose Helicobacter pylori infection in patients with bleeding ulcers has been questioned. The aim of this paper is to evaluate the validity of the CLO test in comparison with histology in diagnosing H. pylori infection in patients with acute upper gastrointestinal bleeding (UGB), irrespective of non‐steroidal anti‐inflammatory drug (NSAID) use.

Level of α-catenin expression in colorectal cancer correlates with invasiveness, metastatic potential, and survival

Background and Objectives: Decreased expression of the E‐cadherin/α‐catenin cell–cell adhesion complex is considered to elicit detachment of tumor cells from primary lesions and development of metastases. The immunohistochemical profile of α‐catenin in colorectal cancer, as well as its correlation with differentiation, lymph node/liver metastasis and patient survival is presented in this study.

Detection of human papillomaviruses in squamous cell carcinomas of the lung

Abstract The aim of this study was to evaluate the possible association of human papillomaviruses (HPV) with the development of squamous cell lung carcinomas (SqCLCs). Tissue material from 52 cases of SqCLCs were studied, and the data were evaluated according to the degree of differentiation, HPV presence and type. Analysis was performed by polymerase chain reaction (PCR) method using consensus primers, and the results were confirmed by subsequent Southern blot hybridization. Overall, the results showed 69% positivity (n=32). Forty-one cases were examined for the presence of specific HPV types (6/11 and 16/18) by hybridization of the PCR products with 32P-labelled probes. HPV 6/11 types were detected in 6 of the 29 positive cases (20.6%). HPV 16/18 types were the most prevalent types, and were detected in 11/29 cases (37.9%: 4/10 of well-differentiated cases, 6/25 of moderately and 1/6 of poorly differentiated carcinomas). Our results confirm the possibility that HPV might play a role in the development of SqCLCs and suggest a possible relation of high-risk HPV16/18 types to tumour differentiation.

WAF1/p21 protein expression is an independent prognostic indicator in superficial and invasive bladder cancer.

The inhibitor of cyclin-dependent kinases WAF1 gene product p21 is able to arrest mammalian cell cycle by mediating p53 and other factors. The prognostic value and interrelationships between p21 expression and various parameters in bladder cancer have not been fully elucidated. We retrospectively investigated the immunohistochemical expression of p21 protein in consecutive paraffin sections from 131 transitional cell carcinomas (TCCs) and related it to p53 protein expression, clinicopathologic parameters, proliferative fraction, and survival. Positivity was displayed in 45% of cases, among which one fourth was accompanied by p53 accumulation. p21 expression was statistically related to advanced T category. No association was shown between p21 and p53 or proliferation rate. Low grade invasive TCCs tended to be more often p21 positive than high grade invasive TCCs. Most superficial tumors displayed neither p21 nor p53 expression, whereas the combined phenotypes p53/p21+ and p53+/p21− predominated among invasive tumors. P21 labeling index emerged by multivariate analysis as the single independent indicator of shortened overall (P = 0.0294) and disease-free (P = 0.0414) survival in superficial TCCs. Conversely, in invasive tumors, loss of p21 expression was a predictor of shortened disease-free survival (P = 0.0234) and was associated with poor outcome when accompanied by p53 accumulation (P = 0.0033). In conclusion, our results indicate that p21 activation occurs early in tumorigenesis, appears associated with invasiveness, and is capable of cell cycle control in TCCs mostly through p53-dependent pathways. Finally, p21 expression, alone or in combination with p53 and irrespective of other clinicopathologic parameters, plays distinct roles in determining clinical outcome in superficial and invasive tumors, suggesting that urothelial bladder cancer represents two different diseases.

Expression of apoptotic and proliferation markers in meningiomas

Fifty‐two intracranial, totally excised meningiomas were immunohistochemically analysed for the expression of bcl‐2 and p53 proteins, in parallel with the assessment of the proliferating cell nuclear antigen labelling index (PCNA LI) and the mitotic index (MI). bcl‐2 was expressed in 26·8 per cent and p53 in 32·6 per cent of the tumours, exhibiting a similar staining pattern, with low levels of immunoreactive cells. The bcl‐2‐positive/p53‐negative subgroup showed a significant association with a benign histological pattern. Expression of bcl‐2 appeared to have no influence on the rate of recurrence; p53 expression was the only factor with prognostic significance for recurrence (p =0·10). There was no interaction between bcl‐2 and p53 expression. The PCNA LI was correlated with the MI and the grade of malignancy, proving to be a useful proliferation marker and an additional indicator of the more anaplastic histological patterns in meningiomas. Proliferation indices appeared to have no correlation with the recurrence rate of totally resected tumours. Meningiomas expressing the bcl‐2 protein presented a high proportion of proliferating cells in S phase. In contrast, all the tumours which recurred had a minimal S‐fraction of proliferating nuclei. These findings may improve our understanding of the interaction between cell proliferation, expression of apoptotic markers, and recurrence in meningiomas.Copyright

Reduced retinoblastoma gene protein to ki-67 ratio is an adverse prognostic indicator for ovarian adenocarcinoma patients

OBJECTIVE Alterations in the retinoblastoma gene (RB-1) are common in human neoplasia. However, the clinical significance of the deregulated expression of RB-1 in ovarian cancer remains undefined. We therefore conducted a retrospective investigation to clarify the relationships of RB-1 gene protein (pRb) to the percentage of cycling cells, clinicopathologic variables, other G1 interacting proteins and prognosis of nonbenign epithelial ovarian tumors. METHODS Paraffin-embedded tissue from 127 nonbenign epithelial ovarian tumors, including 44 of low malignant potential (LMP) and 83 primary ovarian adenocarcinomas, was stained immunohistochemically for pRb, p21(Cip1), p27(Kip1), p53, and Ki-67 antigen (a cell proliferation associated marker). Expression of these markers was correlated with clinicopathologic features and with overall survival of patients with adenocarcinomas. RESULTS pRb levels were significantly lower in LMP tumors than in carcinomas (P = 0.027). In the latter group, pRb expression decreased with increasing grade (I-II vs III) (P = 0.010), advancing stage (I-II vs III) (P < 0.001), and bulk residual disease (P = 0.014). pRb was not related to Ki-67 expression (P > 0.10) or to overall survival (P > 0.10) but a low pRb to Ki-67 ratio emerged as an important indicator of poor survival in univariate analysis in the entire cohort (P = 0.0076) and in the platinum-treated patients (P = 0.0162) as well as in multivariate analysis, along with histologic type and FIGO stage. CONCLUSIONS Diminished pRb levels are related to several clinicopathologic indicators of aggressiveness in ovarian adenocarcinomas. More importantly, pRb expression coupled with the percentage of Ki-67 positive cells is a better prognostic marker than pRb, Ki-67, or other G1 interacting proteins and supplements the information gained from traditional prognosticators.